Response to: Does High Circulating Insulin Drive Body Fat Accumulation?
Consistent with his track record thus far, Stephan Guyenet either misunderstands, or purposefully misrepresents the facts regarding the physiology of obesity.
In his latest blog post, he tries to discredit the "hypothesis" (lol it's not hypothetical) that insulin controls fat storage in the fat cell, and that more insulin signaling in adipose logically leads to more fat accumulation.
To discredit this immutable fact of biology and physiology, he irrationally selects as a model these mutant mice who are severely insulin resistant due to targeted genetic alterations, therefore unable to accumulate body fat as their fat cells are undoubtedly severely IR.
Guyenet presents this almost willfully ignorant position that, because these mice fail to accumulate body fat in the presence of extreme hyperinsulinemia, therefore the "hypothesis" that insulin controls and is a prerequisite for fat cell hypertrophy is incorrect.
It is impossible to be as academically accomplished as he is, and have logic this poor. This is why I am convinced Stephan Guyenet understands the facts very well but misrepresents them; his logic is so poor it would be impossible for him to accomplish what he has in acedemia. No one but a fool would argue - or expect- body fat gain if the subject was severely insulin resistant. The fact he chooses severely, profoundly insulin resistant animals as an example tells us all we need to know about whether or not insulin is instrumental in obesity.
If either of these conditions are not met, obesity is physically impossible.
What Stephan Guyenet has done, is this slight of hand 3 card monte trick where he presents a case where condition 3 is met in spades, but the reader is blinded from the fact that condition 2 is abnormally deficient. A mouse who has had its genetics fucked up to the point where it's adipocyte IR barely work, is not capable of becoming obese. It is insulin signaling in the adipocyte that causes obesity, when combined with other permitting factors such as excessive insulin levels + having the proper genetics to accumulate excessive fat in the fat cell. See link above.
Stephan Guyenet is presenting these rodents as if they are this big revelation, this novel discovery. There is nothing at all novel or unexpectd in the finding that severely insulin resistant people are resistant to obesity. This is completely expected.
We have human analogues of these mice. They have severe, extreme insulin levels, but they are incapable of storing even normal levels of adipose. For example, the genetic conditionLeprechaunism. People are born without functional insulin receptors. Their insulin levels are 80millionty, but yet, they are actually emaciated and extremely small (hence the namesake - leprechaunism - they are small because insulin receptors are required to initiate IGF. This is why diabetic infants are enormous, and fat people often are oversized/have deep voices suggesting growth hormone excess. When insulin is high and receptors are functional-ish, overgrowth occurs IN GENERAL, not just in body fat.) Insulin is required for normal growth, and very high insulin will result in very extreme growth, thus the common observation of macrosomia in infants of diabetic mothers, and why the average neonatal weight is like 20 pounds now, lol. Krispy kremes make huge babies, from glucose + insulin + relatively functional receptors.
Let's look to see what wikipedia has to say about lecprechaunism. Hmm, how might one present if they lacked insulin receptor functionality? Let's find out!
...Physical features include stunted growth (including duringgestation), an enlarged clitoris and breasts in affected females, and an enlarged penis in affected males. In the Journal of Pediatric Medicine, Donohue and Uchida described affected sisters whose growth appeared to have ended in the seventh month of gestation, both born alive but dying before four months of age. Very early death (or spontaneous abortion) is the norm, although sufferers sometimes live longer than a decade.
As the mutation causing the disorder affects insulin receptorfunction, those with the disease are also insulinresistant, with hypoglycemia and profound hyperinsulinemia (very high levels of insulin in the blood)Another feature of the disease is that thesubcutaneousAdipose tissue is markedly diminished. (Contributing to the unusual appearance of affected individuals.)
A much milder form of the disease, in which there is some insulinresistance but normal growth and subcutaneous fat distribution, is also known. It is caused by a less severe mutation of the same gene.
Oh my wordy! So, here we have an unfortunate soul born with no functional IR. This is not like common insulin resistance, which really means "the receptors work, just not that well", and it means" the receptors work, but some tissues work better than others, typically body fat works well but muscle/liver doesn't work as well". No, these poor babies are truly INSULIN RESISTANT, they have like no insulin sensitivity at all.
Interesting, that not only are the infants dwarfed, but, and I quote"the subcutaneous adipose is markedly diminished". It almost suggests that insulin signaling in the fat tissue is required for fat tissue growth, doesn't it? The fact that the fat tissue is so abnormally diminished does suggest that insulin rules fat tissue, doesn't it?
(Regarding the androgenic symptoms -body hair and enlarged genitalia - this is explained by the fact that very high insulin increases DHEA-S from the adrenals which is a potent androgen; this is also why garden variety obese humans, and humans with documented hyperinsulinemia, also present with hyperandrogenism, such as but not limited to PCOS; all humans with excessive insulin will also show signs of excessive androgen production).
If Guyenet wants to understand whether or not insulin drive's body fat accumulation, the only way to test this is to take a non-obese human, who has the fat cell genetics to respond to insulin with obesity, and then to induce upon them the condition of hyperinsulinemia. This is the only way possible to test this. As it is, he is arguing insulin does not control obesity, and he is using subjects that are abnormally resistant to insulin-mediated fattening as their receptors are deficient. Having deficient receptor functionality is practically the same as not having the ligand present at all. It makes no sense. It's grossly illogical. When IR is severe enough, and is present in fat tissue as well, it's almost as if you don't even have insulin in your system, and the person starts to present like a type 1 diabetic with emaciation. The fact Guyenet's mutant mice actually lost weight suggests this is the case.
I want to stress this - hyperinsulinemia is not, not, not sufficient for obesity. AS STATED ABOVE, there must be 3 conditions met, insulin is just one of those conditions. The other two conditions are ad lib food supply, and having genes in your adipocytes which are capable of responding to insulin with obesity - that is to say, becoming extremely hypertrophic, and hyperplastic.
Not all people, or animals, can do this. It is purely a genetic thing, and not all of us have the genes for obesity. No, genes are not the whole story, which is why I am wearing a size 0 today, but genes are an essential prerequisite. You can not massively inject insulin into an organism who's fat cells resist obesity, and expect them to develop obesity. However, if a mad scientist were to implant a little device that dripped insulin into my blood stream 24/7, I would be 300 pounds in short order, because I DO have the fat cell genetics to respond to insulin with this symptom.
A far better model for testing the "hypothesis" (LOL again it's not hypothetical it is scientific fact) that insulin drives/control adipocyte size/fat storage/replication, is humans freely and randomly developing insulinomas.
Observing the weight status of individuals with a random development of a cancerous proliferation of insulin-producing cells is the true test of whether or not insulin mediates obesity. A person with a true insulinoma is otherwise normal, but unfortuantely for them, they have a neoplastic development of pancreatic insulin producing cells, switched in a constant "on" production of insulin. The cells do not work like normal beta cells, they never stop producing insulin, even when the blood glucose is very hypoglycemic. The basal insulin and proinsulin will be multiple times the normal level.
This cancer is heralded by chronic severe hypoglycemia, particularly while fasting, proinsulin & insulin levels which are extremely elevated, and acanthosis nigricans (velvety hyperpigmentation of the skin, which is a growth change specifically caused by excessive insulin binding - it is found in skin folds such as under arms, behind the neck, waist line, groin area, fingers and joints - FYI this symptom is very common in garden variety obese people, many if not most of them have acanthosis nigricans, a sure sign of hyperinsulinemia; I myself had this very badly, I no longer do at all and with time it has almost entirely resolved, but it took several years). Another common, but not ubiquitous symtpom of insulinoma, is obesity, sometimes extreme obesity.
IF IT IS TRUE that insulin does not lead to obesity, does not cause fat cell hypertrophy, then we would expect people with insulinomas to never develop severe obesity, at least not more often than random. This is not the case - obesity is often a sign/symptom of an insulinoma. And, the fact that not ALL people with insulinomas become obese, also supports the fact that the criterion of genetic potential of fat cells to respond to insulin with obesity is required.
Obesity and Insulinoma
In one study of adolescents and adults with insulinomas, 71% reported relief of symptoms with food ingestion and 40% reported weight gain. Patients with insulinomas may become obese, because excess insulin promotes fat production and storage. [774,11989]
We have had poor individuals get gastric mutilation surgeries, only to discover they had an insulinoma all along. No physician tested it, because people caring for the obese think like Guyenet - no one suspects a distinct, isolated, hyperinsulinemia as the cause of hyperphagia and body fat accumulation. Every doctor, especially bariatric ones, assumes it is a food addiction problem. We are brainwashed from birth, by uneducated ignorant morons with no medical training (e.g. Dr Phil and Oprah) to believe we are food addicts and we eat food for emotional reasons. No one seems to believe, suspect, understand, that fat tissue is regulated just like every other organ, eating is a result not a cause of excessive insulin action, and whether or not your fat tissue grows to the size of a house depends on the genes contained in your white fat.
So, the person gets gastric surgery, and suddenly they are chronically hypoglycemic. This occurs because the issue is excessive insulin production independent of food intake, so after surgery the person is chronically hypo as they are incapable of eating. In garden variety obesity (not mediated by insulinoma), the excessive insulin production is reactive to glucose intolerance (i.e. food) so the surgery will not cause this symptom - in fact, it makes their obesity much better and their glucose much more stable. Little does the gastric patient know, a high fat low glucose diet does the same thing and allows you to avoid the numerous complications of surgery.
This also supports the idea that something about excessive insulin signaling itself will induce resistance, which also counter argues against the ever popular CNS-centric line of thought idea that insulin resistance is a result of obesity with no role in etiology. Insulinoma patients are very frequently IR, in spite of the fact their excess insulin is purely of neoplastic origin and not a reaction to some complex hepatic-CNS food addict brain disorder of the sort Guyenet or Kruse might champion, lol.
In summary, Guyenet gets it wrong as usual. Arguing against the essential, vital role of insulin signaling in adipoctes are being a prerequisite for obesity is either madness, ignorance, or deception, take your pick. This is an impossible position to take, so this is why Guyenet's clinical examples are horrid and easily refuted (you're using a genetically defective/modified lab rat organism with no insulin sensitivity to figure out the actions of insulin? Really? That makes sense to you?)
A far better, more illuminating clinical example of the pure biological actions of insulin would be an otherwise normal subject who happens to unfortunately develop a pancreatic neoplasm, with constant on switch of insulin. And as we can see, these individuals OFTEN become fat, sometimes extraordinarily fat, and they also interestingly enough develop resistance to the actions of insulin. When the disorder starts, they are chronically hypoglycemic, but it is not unheard of for them to progress into total resistance to insulin and diabetes. Sounds like a lot of fat people I know.